As in the past the very vigorous and sharply focused objective of the continuation research will be the accelerated discovery and preclinical development of new and structurally unique anticancer drug candidates for the U.S. National Cancer Institute. Emphasis will continue to be devoted to small molecule anticancer constituents isolated from terrestrial arthropods, marine organisms, microorganisms and plants followed by structural determinations, syntheses and/or structural modifications. Special emphasis will be placed on new antineoplastic substances either isolated based on molecular target bioassays or subsequently displaying such potent antiangiogenesis, cancer vascular targeting, tubulin and/or various cancer-implicated kinase (cyclin-dependent, protein kinase C, tyrosine kinase and telomerase) properties as well as exceptionally strong antineoplastic activity. Additional emphasis will be placed on further research necessary to advance the expanding and vitally important clinical trials of the auristatins, bryostatin 1, the dolastatins, and others discovered in our laboratory such as the powerful cancer antiangiogenesis and vascular targeting drugs in the combretastatin (CA4P, CA1P) and other series. Only those leads from confirmed active extracts of arthropods, marine invertebrates, marine and terrestrial plants, and marine as well as terrestrial microorganisms that give maximum promise of yielding new drugs with potential clinical activity will be pursued. The proposed continuation research will provide great assistance to the DCTD/NCI in selecting new anticancer drug candidates and speeding their development toward clinical trials. In summary, the proposed research will be sharply aimed at the discovery and very rapid development of new anticancer drugs for the NCI programs directed at improving human cancer treatments. PUBLIC HEALTH RELEVANCE: In the coming year approximately 600,000 people will die of cancer in the United States alone. The discovery and development of more effective and curative anticancer drugs is a vital component in the global effort to address this devastating health problem. The goal of this project is the discovery and development of novel small molecules from terrestrial arthropods, marine organisms, microorganisms, and plants with sufficient antineoplastic activity to offer the potential for ultimate clinical activity against human cancer.